The present invention is useful in the medicinal field. More particularly, substituted imidazolidinone derivatives of the present invention have an action to stimulate muscarinic acetylcholine receptors M4, and are useful as analgesic for diseases accompanying pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain or neuralgia; or as agents for treating tolerance to narcotic analgesics represented by morphine, dependence on narcotic analgesics represented by morphine, itching, dementia, irritable bowel syndrome, schizophrenia, glaucoma, pollakiuria, urinary incontinence, cholelithiasis, cholecystitis, functional dyspepsia and reflux esophagitis.
Muscarinic agonists represented by acetylcholine are those which stimulate muscarinic acetylcholine receptors. Muscarinic agonists exhibit various pharmacological actions such as analgetic action, mnemonic action and: intraocular tension reducing action. Hence they are potential analgesic, agents for ameliorating symptoms of dementia, treating agents for glaucoma, or the like. However, conventional muscarinic agonists exhibit many side-effects and their clinical application is limited.
Recently, reports are made suggesting that such pharmacological actions of a muscarine agonist are expressed through M4 receptor subtype among muscarinic acetylcholine receptors. For example, it was reported that the analgesic action of muscarinic agonists was blocked by administration of m4 toxin which is an M4-selective antagonist, and also that intracerebral administration of m4 toxin alome caused memory defects [cf. Neuroreport, Vol.9, No.7, pp.1407-1411 (1998)]. It is also suggested, furthermore, that M4 receptors participate in various physiological activities such as amelioration of schizophrenia symptoms, contraction of the gallbladder or relaxation of smooth muscle of the bladder [cf. e.g. Life Sciences, Vol.64, June-July, pp527-534 (1999); Journal of Pharmacology and Experimental Therapeutics, Vol.283, No.2, pp.750-756 (1997); Journal of Autonomic Pharmacology, Vol.18, No.4, pp.195-204 (1998)].
Therefore, substances which selectively stimulate M4 receptors can be expected to have utilities as, for example, analgesic for diseases accompanying pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain or neuralgia; or as agents for treating tolerance to narcotic analgesics represented by morphine, dependence on narcotic analgesics represented by morphine, itching, dementia, irritable bowel syndrome, schizophrenia, glaucoma, pollakiuria, urinary incontinence, cholelithiasis, cholecystitis, functional dyspepsia and reflux esophagitis.
Compounds which are structurally analogous to the compounds of the present invention are disclosed in International Publications, e.g. WO96/13262 and WO99/32481. However, those prior art publications contain no specific disclosure or suggestion about the compounds of the, present invention. Neither do they teach anything at all about the M4 receptors-stimulating action.
The object of the present invention is to provide novel analgesic and agents for treating tolerance to narcotic analgesics represented by morphine, dependence on narcotic analgesics represented by morphine, itching, dementia, irritable bowel syndrome, schizophrenia, glaucoma, pollakiuria, urinary incontinence, cholelithiasis, cholecystitis, functional dyspepsia and reflux esophagitis, which have M4 receptors-stimulating action.
We have discovered that compounds represented by a general formula [I]
[in which A, B, C and D are same or differtent and signify methine group(s) or nitrogen atom, said methine group(s) being optionally substituted with cyano, halogen, hydroxyl, cyclo(lower alkyl), lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, aminosulfonyl, lower alkylaminosulfonyl or di(lower alkyl)aminosulfonyl, or lower alkyl which may have a substituent selected from the group consisting of halogen, hydroxyl, amino, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, lower alkoxy-carbonylamino, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, (lower alkylamino)sulfonylamino, (di-lower alkylamino)sulfonylamino, (lower alkylaminosulfonyl)(lower alkyl)amino and (di-lower alkylaminosulfonyl)(lower alkyl)amino; E signifies oxygen or sulfur; 
are same or different and signify C3-C9 mono- or bi-cyclic aliphatic nitrogen-containing heterocyclic group(s) which may be substituted with halogen or lower alkyl; R1 signifies lower alkenyl, lower alkynyl, cyclo(lower alkyl), lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, aminosulfonyl, lower alkylaminosulfonyl or di(lower alkyl)aminosulfonyl, or lower alkylsulfonyl which may be substituted with halogen, hydroxyl or oxo, or lower alkyl which may have a substituent selected from the group consisting of cyano, halogen, hydroxyl, oxo, amino, cyclo(lower alkyl), optionally fluorine-substituted lower alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, lower alkylsulfonylamino, (lower alkylcarbamoyl)amino, (di-lower alkylcarbamoyl)amino, (lower alkylamino)sulfonylamino and (di-lower alkylamino)sulfonylamino; and R2 signifies lower alkyl] possess high M4 receptors-stimulating action and are useful as analgesic for diseases accompanying pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain or neuralgia; or as agents for treating tolerance to narcotic analgesics represented by morphine, dependence on narcotic analgesics represented by morphine, itching, dementia, irritable bowel, syndrome, schizophrenia, glaucoma, pollakiuria, urinary incontinence, cholelithiasis, cholecystitis, functional dyspepsia and reflux esophagitis, and completed the present invention.
The present invention relates to those compounds represented by Formula [I], salts thereof, their production processes and uses.
The symbols and the terms used in the present specification shall be explained.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine and iodine atoms.
xe2x80x9cLower alkylxe2x80x9d means a C1-C6 linear or branched alkyl group, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl groups.
xe2x80x9cLower alkenylxe2x80x9d means a C2-C6 linear or branched alkenyl group, examples of which include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl and 4-pentenyl groups.
xe2x80x9cLower alkynylxe2x80x9d means a C2-C6 linear or branched alkynyl group, examples of which include ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-pentynyl, 3-pentynyl and 4-pentynyl groups.
xe2x80x9cCyclo(lower alkyl)xe2x80x9d means a C3-C6 cycloalkyl group, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
xe2x80x9cLower alkylaminoxe2x80x9d means an amino group which is mono-substituted with an above-named lower alkyl group, examples of which include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and tert-butylamino groups.
xe2x80x9cDi(lower alkyl)aminoxe2x80x9d means an amino group which is di-substituted with above-named lower alkyl group(s), examples of which include dimethylamino, diethylamino, ethylmethylamino, dipropylamino, methylpropylamino and diisopropylamino groups.
xe2x80x9cLower alkythioxe2x80x9d means an alkylthio group having an above-named lower alkyl group, examples of which include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio and tert-butylthio groups.
xe2x80x9cLower alkylsulfinylxe2x80x9d means an alkylsulfinyl group having an aforesaid lower alkyl group, examples of which include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, sec-butylsulfinyl and tert-butylsulfinyl groups.
xe2x80x9cLower alkylsulfonylxe2x80x9d means an alkylsulfonyl group having an aforesaid lower alkyl group, examples of which include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
xe2x80x9cLower alkoxyxe2x80x9d means an alkoxy group having an aforesaid alkyl group, i.e., a C1-C6 alkoxy group, examples of which include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and pentyloxy groups.
xe2x80x9cOptionally fluorine-substituted lower alkoxyxe2x80x9d means an aforesaid lower alkoxy group whose substitutable, optional position(s) may be substituted with one or two or more, preferably 1-3, fluorine atoms, examples of which include, in addition to the above-exemplified alkoxy groups, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,2-difuoroethoxy and 2,2-difluoroethoxy groups.
xe2x80x9cLower alkanoylxe2x80x9d means an alkanoyl group having an aforesaid lower alkyl group, i.e., a C2-C7 alkanoyl group, examples of which include acetyl propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl groups.
xe2x80x9cLower alkoxycarbonylxe2x80x9d means an alkoxycarbonyl group having an aforesaid lower alkoxy group, i.e., a C2-C7 alkoxycarbonyl group, examples of which include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and pentyloxycarbonyl groups.
xe2x80x9cLower alkylcarbamoylxe2x80x9d means a carbamoyl group which is mono-substituted with an aforesaid lower alkyl group, examples of which include methylcabamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, sec-butylcarbamoyl and tert-butylcarbamoyl groups.
xe2x80x9cDi(lower alkyl)carbamoylxe2x80x9d means a carbamoyl group which is di-substituted with aforesaid lower alkyl group(s), examples of which include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, dipropylcarbamoyl, methylpropylcarbamoyl and diisopropylcarbamoyl groups.
xe2x80x9cLower alkylaminosulfonylxe2x80x9d means an alkylaminosulfonyl group having an aforesaid lower alkylamino group, examples of which include methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, sec-butylaminosulfonyl and tert-butylaminosulfonyl groups.
xe2x80x9cDi(lower alkyl)aminosulfonylxe2x80x9d means a dialkylaminosulfonyl group having an aforesaid di-lower alkylamino group, examples of which include dimethylaminosulfonyl, diethylaminosulfonyl, ethylmethylaminosulfonyl, dipropylaminosulfonyl, methylpropylaminosulfonyl and diisopropylaminosulfonyl groups.
xe2x80x9cLower alkylcarbamoyloxyxe2x80x9d means an alkylcarbamoyloxy group having an aforesaid lower alkylcarbamoyl group, examples of which include methylcarbamoyloxy, ethylcarbamoyloxy, propylcarbamoyloxy, isopropylcarbamoyloxy, butylcarbamoyloxy, sec-butylcarbamoyloxy and tert-butylcarbamoyloxy groups.
xe2x80x9cDi(lower alkyl)carbamoyloxyxe2x80x9d means a dialkylcarbamoyloxy group having an aforesaid di-lower alkylcarbamoyl group, examples of which include dimethylcarbamoyloxy, diethylcarbamoyloxy, ethylmethylcarbamoyloxy, dipropylcarbamoyloxy, methylpropylcarbamoyloxy and diisopropylcarbamoyloxy groups.
xe2x80x9cLower alkoxycarbonylaminoxe2x80x9d means an amino group which is mono-substituted with an aforesaid lower alkoxycarbonyl group, examples of which include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylaino, isobutoxycarbonylamino, tert-butoxycarbonylamino and pentyloxycarbonylamino groups.
xe2x80x9c(Lower alkylamino)sulfonylaminoxe2x80x9d means an amino group which is mono-substituted with an aforesaid lower alkylaminosulfonyl group, examples of which include (methylamino)sulfonylamino, (ethylamino)sulfonylamino, (propylamino)sulfonylamino, (isopropylamino)sulfonylamino, (butylamino)sulfonylamino, (sec-butylamino)sulfonylamino and (tert-butylamino)sulfonylamino groups.
xe2x80x9c(Di-lower alkylamino)sulfonylaminoxe2x80x9d means an amino group which is mono-substituted with an aforesaid di-lower alkylaminosulfonyl group, examples of which include (dimethylamino)sulfonylamino, (diethylamino)sulfonylamino, (ethylmethylamino)sulfonylamino, (dipropylamino)sulfonylamino, (methylpropylamino)sulfonylamino and (diisopropylamino)sulfonylamino groups.
xe2x80x9c(Lower alkylaminosulfonyl)(lower alkyl)aminoxe2x80x9d means an amino group which is substituted with an aforesaid lower alkylaminosulfonyl group and an aforesaid lower alkyl group, examples of which include methyl(methylaminosulfonyl)amino, (ethylamino-sulfonyl)methylamino groups.
xe2x80x9c(Di-lower alkylaminosulfonyl)(lower alkyl)aminoxe2x80x9d means an amino group which is substituted with an aforesaid di-lower alkylaminosulfonyl group and an aforesaid lower alkyl group, examples of which include (dimethylaminosulfonyl)methylamino and (diethylaminosulfonyl)methylamino groups.
xe2x80x9cMono- or bi-cyclic aliphatic nitrogen-containing heterocyclic groupxe2x80x9d means a mono- or bi-cyclic group which is a saturated aliphatic heterocyclic group containing at least one nitrogen atom as a ring-forming member, examples of which include those groups expressed by the following formulae: 
(in which m signifies an integer of 3-7; q, r and t, which may be same or different, each signifies an integer of 0-3; s signifies an integer of 1-4; and the sum of q, r, s and t not exceeding 7).
xe2x80x9cLower alkylsulfonylaminoxe2x80x9d means an amino group which is mono-substituted with an aforesaid lower alkylsulfonyl group, examples of which include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, sec-butylsulfonylamino and tert-butylsulfonylamino groups.
xe2x80x9c(Lower alkylcarbamoyl)aminoxe2x80x9d means an amino group which is mono-substituted with an aforesaid lower alkylcarbamoyl group, examples of which include (methylcarbamoyl)amino, (ethylcarbamoyl)amino, (propylcarbamoyl)amino, (isopropylcarbamoyl)amino, (butylcarbamoyl)amino, (sec-butylcarbamoyl)amino and (tert-butylcarbamoyl)amino groups.
xe2x80x9c(Di-lower alkylcarbamoyl)aminoxe2x80x9d means an amino group which is mono-substituted with an aforesaid di-lower alkylcarbamoyl group, examples of which include (dimethylcarbamoyl)amino, (diethylcarbamoyl)amino, (ethylmethylcarbamoyl)amino, (dipropylcarbamoyl)amino, (methylpropylcarbamoyl)amino and (diisopropylcarbamoyl)amino groups.
xe2x80x9cSaltsxe2x80x9d of those compounds which are represented by the general formula [I] means customary, pharmaceutically acceptable ones, for examples, acid addition salts at the basic heterocyclic groups. As such acid addition salts, for example, inorganic acid salts, e.g., hydrochloride, hydrobromide, sulfate, nitrate, phosphate, perchlorate and the like; organic acid salts such as maleate, fumarate, tartarate, citrate, ascorbate, benzoate, trifluoroacetate and the like; and sulfonic acid salts such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate and the like may be named.
xe2x80x9cTreating agentxe2x80x9d means drugs which are used for treatment and/or prophylaxis of various diseases.
For disclosing the compounds of the present invention, which are represented by the general formula [I], more specifically, those marks or symbols used in said formula [I] are explained in further details, referring to preferred specific examples.
Those compounds of the general formula [I] of the present invention in occasions may have stereoisomers such as optical isomers, diastereomers, geometrical isomers and the like, depending on the conditions of their substituents. The compounds of the general formula [I] of the present invention cover all of these stereoisomers and their mixtures.
To avoid any unnecessary confusion, position numbers of the 2-oxoimidazole ring moiety of the compounds of the present invention are set as in the following formula [a] throughout in the specification, for nominating individual compounds and providing other explanations. 
A, B, C and D are same or differtent and signify methine group(s) or nitrogen atom, said methine group(s) being optionally substituted with cyano, halogen, hydroxyl, cyclo(lower alkyl), lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, aminosulfonyl, lower alkylaminosulfonyl or di(lower alkyl)aminosulfonyl, or lower alkyl which may have a substituent selected from the group consisting of halogen, hydroxyl, amino, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, lower alkoxy carbonylamino, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, (lower alkylamino)sulfonylamino, (di-lower alkylamino)sulfonylamino, (lower alkylaminosulfonyl)(lower alkyl)amino and (di-lower alkylaminosulfonyl)(lower alkyl)amino.
As the substituent halogen atom, for example, fluorine, chlorine and bromine atoms are preferred.
As the substituent cyclo(lower alkyl), for example, cyclopropyl and cyclobutyl groups are preferred.
As the substituent lower alkylthio, for example, methylthio, ethylthio and propylthio groups are preferred.
As the substituent lower alkylsulfinyl, for example, methylsulfinyl and ethylsulfinyl groups are preferred.
As the substituent lower alkylsulfonyl, for example, methylsulfonyl, ethylsulfonyl and propylsulfonyl groups are preferred.
As the substituent optionally fluorine-substituted lower alkoxy, for example, methoxy, ethoxy, propoxy, fluoromethoxy and 2,2-difluoroethoxy groups are preferred.
As the substituent lower alkanoyl, for example, acetyl, propionyl and butyryl groups are preferred.
As the substituent lower alkoxycarbonyl, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl groups are preferred.
As the substituent lower alkylcarbamoyl, for example, methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl groups are preferred.
As the substituent di(lower alkyl)carbamoyl, for example, dimethylcarbamoyl, diethylcarbamoyl and dipropylcarbamoyl groups are preferred.
As the substituent lower alkylaminosulfonyl, for example, methylaminosulfonyl and ethylaminosulfonyl groups are preferred.
As the substituent di(lower alkyl)aminosulfonyl, for example, dimethylaminosulfonyl and diethylaminosulfonyl groups are preferred.
The substituent xe2x80x9clower alkyl which may have a substituent selected from the group consisting of halogen, hydroxyl, amino, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, lower alkoxycarbonylamino, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, (lower alkylamino)sulfonylamino, (di-lower alkylamino)sulfonylamino, (lower alkylaminosulfonyl)(lower alkyl)amino and (di-lower alkylaminosulfonyl)(lower alkyl)aminoxe2x80x9d means named lower alkyl groups which are unsubstituted and those named lower alkyl groups which are substituted at substitutable, optional position(s). One, two or more, preferably one or two, same or different substituents can be selected from the group consisting of halogen, hydroxyl, amino, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, lower alkoxy carbonylamino, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, (lower alkylamino)sulfonylamino, (di-lower alkylamino)sulfonylamino, (lower alkylaminosulfonyl)(lower alkyl)amino and (di-lower alkylaminosulfonyl)(lower alkyl)amino.
As the substituent halogen, for example, fluorine atom is preferred.
As the substituent lower alkylamino, for example, methylamino and ethylamino groups are preferred.
As the substituent di(lower alkyl)amino, for example, dimethylamino and diethylamino groups are preferred.
As the substituent lower alkylthio, for example, methylthio and ethylthio groups are preferred.
As the substituent lower alkylsulfinyl, for example, methylsulfinyl and ethylsulfinyl groups are preferred.
As the substituent lower alkylsulfonyl, for example, methylsulfonyl, ethylsulfonyl and propylsulfonyl groups are preferred.
As the substituent optionally fluorine-substituted lower alkoxy, for example, methoxy, ethoxy, propoxy, fluoromethoxy and 2,2-difluoroethoxy groups are preferred.
As the substituent lower alkanoyl, for example, acetyl and propionyl groups are preferred.
As the substituent lower alkoxycarbonyl, for example, methoxycarbonyl and ethoxycarbonyl groups are preferred.
As the substituent lower alkylcarbamoyl, for example, methylcarbamoyl and ethylcarbamoyl groups are preferred.
As the substituent di(lower alkyl)carbamoyl, for example, dimethylcarbamoyl group is preferred.
As the substituent lower alkylcarbamoyloxy, for example, methylcarbamoyloxy group is preferred.
As the substituent di(lower alkyl)carbamoyloxy, for example, dimethylcarbamoyloxy group is preferred.
As the substituent lower alkoxycarbonylamino, for example, methoxycarbonylamino and ethoxycarbonylamino groups are preferred.
As the substituent lower alkylaminosulfonyl, for example, methylaminosulfonyl and ethylaminosulfonyl groups are preferred.
As the substituent di(lower alkyl)aminosulfonyl, for example, dimethylaminosulfonyl and diethylaminosulfonyl groups are preferred.
As the substituent (lower alkylamino)sulfonylamino, for example, (methylamino)sulfonylamino and (ethylamino)sulfonylamino groups are preferred.
As the substituent (di-lower alkylamino)sulfonylamino, for example, (dimethylamino)sulfonylamino and (diethylamino)sulfonylamino groups are preferred.
As the substituent (lower alkylaminosulfonyl)(lower alkyl)amino, for example, methyl(methylaminosulfonyl)amino group is preferred.
As the substituent (di-lower alkylaminosulfonyl)(lower alkyl)amino, for example, (dimethylaminosulfonyl)methylamino group is preferred.
As the substituents on said lower alkyl group, for example, halogen, hydroxyl, amino, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, lower alkoxycarbonylamino, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, (lower alkylamino)sulfonylamino, (di-lower alkylamino)sulfonylamino groups are preferred. In particular, lower alkylsulfonyl and lower alkoxycarbonylamino groups are preferred.
As the xe2x80x9clower alkylxe2x80x9d itself which may have above substituent(s), for example, methyl, ethyl, propyl, in particular, methyl, are preferred.
Therefore, preferred examples of those optionally substituted lower alkyl groups include, methyl, ethyl, fluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2-hydroxyethyl, 2-aminoethyl, 2-methylaminoethyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, methylthiomethyl, methylsulfinylmethyl, methylsulfonylmethyl, ethylsulfonylmethyl, propylsulfonylmethyl, 2-methylsulfonylethyl, 2-ethylsulfonylethyl, methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, acetylmethyl, propionylmethyl, 2-acetylethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, carbamoylmethyl, 2-carbamoylethyl, methylcarbamoylmethyl, ethylcarbamoylmethyl, 2-(methylcarbamoyl)ethyl, dimethylcarbamoylmethyl, 2-(dimethylcarbamoyl)ethyl, methylcarbamoyloxymethyl, 2-(methylcarbamoyloxy)ethyl, dimethylcarbamoyloxymethyl, (methoxycarbonylamino)methyl, (ethoxycarbonylamino)methyl, 2-(methoxycarbonylamino)ethyl, 2-(ethoxycarbonylamino)ethyl, aminosulfonylmethyl, methylaminosulfonylmethyl, dimethylaminosulfonylmethyl, 2-(dimethylaminosulfonyl)ethyl, [(methylaminosulfonyl)amino]methyl and [(dimethylaminosulfonyl)amino]methyl. Of those, methyl, methylsulfonylmethyl, ethylsulfonylmethyl and (methoxycarbonylamino)methyl groups are particularly preferred.
As the substituents on the methine group, for example, halogen, hydroxyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, di(lower alkyl)carbamoyl, di(lower alkyl)aminosulfonyl and those optionally substituted lower alkyl groups are preferred.
In particular, halogen, hydroxyl, lower alkylsulfonyl, and above-named optionally substituted lower alkyl groups are preferred.
As A, B, C and D, same or different methine groups which may have above-named substituent groups are preferred.
Accordingly, as the groups represented by the formula 
preferred are those formed from, for example,
1,3-dihydro-2H-benzimidazol-2-one,
4-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
6-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
7-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
4-chloro-1,3-dihydro-2H-benzimidazol-2-one,
5-chloro-1,3-dihydro-2H-benzimidazol-2-one,
6-chloro-1,3-dihydro-2H-benzimidazol-2-one,
7-chloro-1,3-dihydro-2H-benzimidazol-2-one,
5-bromo-1,3-dihydro-2H-benzimidazol-2-one,
4-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
5-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
6-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
7-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
4-methyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methyl-1,3-dihydro-2H-benzimidazol-2-one,
6-methyl-1,3-dihydro-2H-benzimidazol-2-one,
7-methyl-1,3-dihydro-2H-benzimidazol-2-one,
4-ethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-ethyl-1,3-dihydro-2H-benzimidazol-2-one,
6-ethyl-1,3-dihydro-2H-benzimidazol-2-one,
7-ethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-propyl-1,3-dihydro-2H-benzimidazol-2-one,
5-propyl-1,3-dihydro-2H-benzimidazol-2-one,
6-propyl-1,3-dihydro-2H-benzimidazol-2-one,
7-propyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylthio-1,3-dihydro-2H-benzimidazol-2-one,
5-methylthio-1,3-dihydro-2H-benzimidazol-2-one,
6-methylthio-1,3-dihydro-2H-benzimidazol-2-one,
7-methylthio-1,3-dihydro-2H-benzimidazol-2-one,
4-ethylthio-1,3-dihydro-2H-benzimidazol-2-one,
5-ethylthio-1,3-dihydro-2H-benzimidazol-2-one,
4-propylthio-1,3-dihydro-2H-benzimidazol-2-one,
5-propylthio-1,3-dihydro-2H-benzimidazol-2-one,
4-methylsulfinyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylsulfinyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
6-methylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
7-methylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-ethylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
5-ethylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
6-ethylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
7-ethylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-propylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
5-propylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
6-propylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methoxy-1,3-dihydro-2H-benzimidazol-2-one,
5-methoxy-1,3-dihydro-2H-benzimidazol-2-one,
6-methoxy-1,3-dihydro-2H-benzimidazol-2-one,
7-methoxy-1,3-dihydro-2H-benzimidazol-2-one,
4-ethoxy-1,3-dihydro-2H-benzimidazol-2-one,
5-ethoxy-1,3-dihydro-2H-benzimidazol-2-one,
6-ethoxy-1,3-dihydro-2H-benzimidazol-2-one,
7-ethoxy-1,3-dihydro-2H-benzimidazol-2-one,
4-propoxy-1,3-dihydro-2H-benzimidazol-2-one,
5-propoxy-1,3-dihydro-2H-benzimidazol-2-one,
4-acetyl-1,3-dihydro-2H-benzimidazol-2-one,
5-acetyl-1,3-dihydro-2H-benzimidazol-2-one,
6-acetyl-1,3-dihydro-2H-benzimidazol-2-one,
4-propionyl-1,3-dihydro-2H-benzimidazol-2-one,
5-propionyl-1,3-dihydro-2H-benzimidazol-2-one,
4-butyryl-1,3-dihydro-2H-benzimidazol-2-one,
5-butyryl-1,3-dihydro-2H-benzimidazol-2-one,
4-methoxycarbonyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methoxycarbonyl-1,3-dihydro-2H-benzimidazol-2-one,
6-methoxycarbonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-ethoxycarbonyl-1,3-dihydro-2H-benzimidazol-2-one,
5-ethoxycarbonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-propoxycarbonyl-1,3-dihydro-2H-benzimidazol-2-one,
5-propoxycarbonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
6-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
4-ethylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
5-ethylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
4-propylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
5-propylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
4-dimethylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
5-dimethylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
4-diethylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
5-diethylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
4-dipropylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
5-dipropylcarbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
4-aminosulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
5-aminosulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylaminosulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylaminosulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-dimethylaminosulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
5-dimethylaminosulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-fluoromethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-fluoromethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-fluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-fluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-(2,2-difluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2,2-difluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-aminomethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-aminomethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylaminomethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylaminomethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-dimethylaminomethyl-1,3-dihydro-2H benzimidazol-2-one,
5-dimethylaminomethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylthiomethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylthiomethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylsulfinylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylsulfinylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylsulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylsulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-ethylsulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-ethylsulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-propylsulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-propylsulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-methylsulfonylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-methylsulfonylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-ethylsulfonylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-ethylsulfonylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-methoxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methoxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-ethoxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-ethoxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-propoxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-propoxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-methoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-methoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-ethoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-ethoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-acetylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-acetylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-propionylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-propionylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-acetylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-acetylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-methoxycarbonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methoxycarbonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-ethoxycarbonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-ethoxycarbonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-methoxycarbonylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-methoxycarbonylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-ethoxycarbonylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-ethoxycarbonylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-(methoxycarbonylamino)methyl-1,3-dihydro-2H-benzimidazol-2-one
5-(methoxycarbonylamino)methyl-1,3-dihydro-2H-benzimidazol-2-one
4-(ethoxycarbonylamino)methyl-1,3-dihydro-2H-benzimidazol-2-one,
5-(ethoxycarbonylamino)methyl-1,3-dihydro-2H-benzimidazol-2-one,
4-[2-(methoxycarbonylamino)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
5-[2-(methoxycarbonylamino)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
4-[2-(ethoxycarbonylamino)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
4-[2-(ethoxycarbonylamino)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
4-carbamoylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-carbamoylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-carbamoylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-carbamoylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-methylcarbamoylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylcarbamoylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-ethylcarbamoylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-ethylcarbamoylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-[2-(methylcarbamoyl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
5-[2-(methylcarbamoyl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
4-dimethylcarbamoylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-dimethylcarbamoylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-[2-(dimethylcarbamoyl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
5-[2-(dimethylearbamoyl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
4-methylcarbamoyloxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylcarbamoyloxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-[2-(methylcarbamoyloxy)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
5-[2-(methylcarbamoyloxy)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
4-dimethylcarbamoyloxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-dimethylcarbamoyloxymethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-aminosulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-aminosulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylaminosulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylaminosulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-dimethylaminosulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-dimethylaminosulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-[2-(dimethylaminosulfonyl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
5-[2-(dimethylaminosulfonyl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
4-[(methylaminosulfonyl)amino]methyl-1,3-dihydro-2H-benzimidazol-2-one,
5-[(methylaminosulfonyl)amino]methyl-1,3-dihydro-2H-benzimidazol-2-one,
4-[(dimethylaminosulfonyl)amino]methyl-1,3-dihydro-2H-benzimidazol-2-one, and
5-[(dimethylaminosulfonyl)amino]methyl-1,3-dihydro-2H-benzimidazol-2-one,
Of those, groups formed of 1,3-dihydro-2H-benzimidazol-2-one,
4-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
6-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
5-bromo-1,3-dihydro-2H-benzimidazol-2-one,
4-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
5-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
6-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
5-methyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylsulfonyl-1,3-dihydro-2H-benzimidazol-2-one,
4-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
5-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
4-aminomethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-aminomethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylsulfinylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
5-methylsulfinylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-methylsulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one,
4-ethylsulfonylmethyl-1,3-dihydro-2H-benzimidazol-2-one, and
4-(methoxycarbonylamino)methyl-1,3-dihydro-2H-benzimidazol-2-one are particularly preferred.
E meaning oxygen atom or sulfur atom, oxygen atom is the preferred. 
are same or different, and signify C3-C9 mono- or bi-cyclic aliphatic nitrogen-containing heterocyclic group(s) which may be substituted with halogen or lower alkyl. 
links with the vicinal group which is expressed by 
on a substitutable, optional ring carbon atom, and links with the group expressed by 
on a ring nitrogen atom. 
links with the vicinal 
on a substitutable, optional ring carbon atom, and links with the group expressed by 
on a ring nitrogen atom.
xe2x80x9cC3-C9 mono- or bi-cyclic aliphatic nitrogen-containing heterocyclic group(s) which may be substituted with halogen or lower alkylxe2x80x9d means named C3-C9 mono- or bi-cyclic aliphatic nitrogen-containing heterocyclic groups which are unsubstituted or named C3-C9 mono- or bi-cyclic aliphatic nitrogen-containing heterocyclic groups which have substituent(s) at their substitutable, optional position(s), one, two or more, preferably one or two, same or different substituents being selected from the group consisting of halogen and lower alkyl.
As the substituent halogen, for example, fluorine and chlorine atoms are preferred.
As the substituent lower alkyl, for example, methyl, ethyl and propyl groups are preferred.
As C3-C9 mono- or bi-cyclic aliphatic nitrogen-containing heterocyclic groups of 
which may be same or different, for example, those groups represented by 
(in which m, q, r, s and t have the earlier given significations), more specifically, for example, azetidine-1,3-di-yl, piperidine-1,4-di-yl, hexahydroazepine-1,4-di-yl, 3-azabicyclo[3.3.0]octane-3,7-di-yl and 8-azabicyclo[3.2.1]octane-3,8-di-yl groups are preferred. In particular, piperidine-1,4-di-yl group is preferred.
Therefore, as 
which may be same or different, for example, azetidine-1,3-di-yl, pyrrolidine-1,3-di-yl, piperidine-1,3-di-yl, piperidine-1,4-di-yl, 3-fluoropiperidine-1,4-di-yl, 4-methylpiperidine-1,4-di-yl, hexahydroazepine-1,3-di-yl, hexahydroazepine-1,4-di-yl, 3-azabicyclo[3.3.0]octane-3,7-di-yl and 8-azabicyclo[3.2.1]octane-3,8-di-yl groups are preferred. In particular, azetidine-1,3-di-yl, piperidine-1,4-di-yl, 3-fluoropiperidine-1,4-di-yl, 4-methyl-piperidine-1,4-di-yl, hexahydroazepine-1,4-di-yl, 3-azabicyclo[3.3.0]octane-3,7-di-yl and 8-azabicyclo[3.2.1]octane-3,8-di-yl groups are preferred. It is particularly preferred that both of 
are piperidine-1,4-di-yl groups.
R1 signifies lower alkenyl, lower alkynyl, cyclo(lower alkyl), lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, aminosulfonyl, lower alkylaminosulfonyl or di(lower alkyl)aminosulfonyl, or lower alkylsulfonyl which may be substituted with halogen, hydroxyl or oxo, or lower alkyl which may have a substituent selected from the group consisting of cyano, halogen, hydroxyl, oxo, amino, cyclo(lower alkyl), optionally fluorine-substituted lower alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, lower alkylsulfonylamino, (lower alkylcarbamoyl)amino, (di-lower alkylcarbamoyl)amino, (lower alkylamino)sulfonylamino and (di-lower alkylamino)sulfonylamino.
When R1 is lower alkenyl, for example, vinyl, 1-propenyl, 2-propenyl and 3-methyl-2-butenyl groups are preferred.
When R1 is lower alkynyl, for example, ethynyl and 2-propynyl groups are preferred.
When R1 is cyclo (lower alkyl), for example, cyclopropyl, cyclobutyl and cyclopentyl groups are preferred.
When R1 is lower alkanoyl, for example, acetyl and propionyl groups are preferred.
When R1 is lower alkoxycarbonyl, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl groups are preferred.
When R1 is lower alkylcarbamoyl, for example, methylcarbamoyl and ethylcarbamoyl groups are preferred.
When R1 is di(lower alkyl)carbamoyl, for example, dimethylcarbamoyl and diethylcarbamoyl groups are preferred.
When R1 is lower alkylaminosulfonyl, for example, methylaminosulfonyl and ethylaminosulfonyl groups are preferred.
When R1 is di(lower alkyl)aminosulfonyl, for example, dimethylaminosulfonyl and diethylaminosulfonyl groups are preferred.
xe2x80x9cLower alkylsulfonyl which may be substituted with halogen, hydroxyl or oxoxe2x80x9d as R1 means unsubstituted lower alkylsulfonyl groups as above-named, and those lower alkylsulfonyl groups having one or two or more, preferably one to three, substituents which may be same or different and are selected from the group consisting of halogen, hydroxyl and oxo, at their substitutable, oprional position(s).
As the substituent halogen, for example, fluorine atom is preferred.
As the xe2x80x9clower alkylsulfonylxe2x80x9d per se of said optionally substituted lower alkylsulfonyl, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and butylsulfonyl groups are preferred.
Therefore, as examples of those optionally substituted lower alkylsulfonyl, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, fluoromethylsulfonyl, trifluoromethylsulfonyl, (2-hydroxyethyl)sulfonyl, (2-chloroethyl)sulfonyl, (2-oxopropyl)sulfonyl, (2,2,2-trifluoroethyl)sulfonyl and (3,3,3-trifluoropropyl)sulfonyl groups can be named. Of those, the preferred are methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, butylsulfonyl, (2-hydroxyethyl)sulfonyl and (2,2,2-trifluoroethyl)sulfonyl groups, inter alia, methylsulfonyl group.
xe2x80x9cLower alkyl which may have a substituent selected from the group consisting of cyano, halogen, hydroxyl, oxo, amino, cyclo(lower alkyl), optionally fluorine-substituted lower alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, lower alkylsulfonylamino, (lower alkylcarbamoyl)amino, (di-lower alkylcarbamoyl)amino, (lower alkylamino)sulfonylamino and (di-lower alkylamino)sulfonylaminoxe2x80x9d as R1 means unsubstituted lower alkyl groups as above-named, and those lower alkyl groups having one, two or more, preferably one to three, substituents which may be same or different, at their substitutable, optional position(s), said substituent(s) being selected from the group consisting of cyano, halogen, hydroxyl, oxo, amino, cyclo(lower alkyl), optionally fluorine-substituted lower alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, lower alkylsulfonylamino, (lower alkylcarbamoyl)amino, (di-lower alkylcarbamoyl)amino, (lower alkylamino)sulfonylamino and, (di-lower alkylamino)sulfonylamino.
As the substituent halogen, for example, fluorine atom is preferred.
As the substituent cyclo (lower alkyl), for example, cyclopropyl and cyclobutyl groups are preferred.
As the substituent optionally fluorine-substituted lower alkoxy, for example, methoxy, ethoxy, propoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy groups are preferred.
As the substituent lower alkylamino, for example, methylamino and ethylamino groups are preferred.
As the substituent di(lower alkyl)amino, for example, dimethylamino and diethylamino groups are preferred.
As the substituent lower alkylthio, for example, methylthio and ethylthio groups are preferred.
As the substituent lower alkyl sulfinyl, for example, methylsulfinyl and ethylsulfinyl groups are preferred.
As the substituent lower alkylsulfonyl, for example, methylsulfonyl and ethylsulfonyl groups are preferred.
As the substituent lower alkoxycarbonyl, for example, methoxycarbonyl and ethoxycarbonyl groups are preferred.
As the substituent lower alkylcarbamoyl, for example, methylcarbamoyl and ethylcarbamoyl groups are preferred.
As the substituent di(lower alkyl)carbamoyl, for example, dimethylcarbamoyl and diethylcarbamoyl groups are preferred.
As the substituent lower alkylcarbamoyloxy, for example, methylcarbamoyloxy and ethylcarbamoyloxy groups are preferred.
As the substituent di(lower alkyl)carbamoyloxy, for example, dimethylcarbamoyloxy and diethylcarbamoyloxy groups are preferred.
As the substituent lower alkylaminosulfonyl, for example, methylaminosulfonyl and ethylaminosulfonyl groups are preferred.
As the substituent di(lower alkyl)aminosulfonyl, for example, dimethylaminosulfonyl and diethylaminosulfonyl groups are preferred.
As the substituent lower alkylsulfonylamino, for example, methylsulfonylamino and ethylsulfonylamino groups are preferred.
As the substituent (lower alkylcarbamoyl)amino, for example, (methylcarbamoyl)amino and (ethylcarbamoyl)amino groups are preferred.
As the substituent (di-lower alkylcarbamoyl)amino, for example, (dimethylcarbamoyl)amino and (diethylcarbamoyl)amino groups are preferred.
As the substituent (lower alkylamino)sulfonylamino, for example, (methylamino)sulfonylamino and (ethylamino)sulfonylamino groups are preferred.
As the substituent (di-lower alkylamino)sulfonylamino, for example, (dimethylamino)sulfonylamino and (diethylamino)sulfonylamino groups are preferred.
As the substituent(s) on R1 lower alkyl, for example, cyano, halogen, hydroxyl, oxo, amino, cyclo(lower alkyl), optionally fluorine-substituted lower alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfonyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylsulfonylamino, (di-lower alkylcarbamoyl)amino, (lower alkylamino)sulfonylamino and (di-lower alkylamino)sulfonylamino groups are preferred.
As R1 lower alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups are preferred.
Therefore, as those optionally substituted lower alkyl as R1, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyanomethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-oxopropyl, 2-oxobutyl, 2-aminoethyl, cyclopropylmethyl, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, methylthiomethyl, 2-methylthioethyl, methylsulfonylmethyl, 2-methylsulfonylethyl, ethoxycarbonylmethyl, 2-(carbamoyloxy)ethyl, 2-(methylsulfonylamino)ethyl, 2-(dimethylcarbamoylamino)ethyl, 2-(methylaminosulfonylamino)ethyl and 2-[(dimethylaminosulfonyl)-amino]ethyl groups may be named. Of those, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-fluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 2-oxopropyl, 2-oxobutyl, 2-aminoethyl, cyclopropylmethyl, 2-ethoxyethyl, 2-methylaminoethyl, 2-dimethylamioethyl, methylthiomethyl, 2-methylthioethyl, methylsulfonylmethyl, 2-methylsulfonylethyl, ethoxycarbonylmethyl and 2-(carbamoyloxy)ethyl groups are preferred.
As R1, for example, lower alkenyl, cyclo(lower alkyl), lower alkoxycarbonyl or carbamoyl; lower alkylsulfonyl which may be substituted with halogen, hydroxyl or oxo; and above optionally substituted lower alkyl groups are preferred. In particular, lower alkylsulfonyl which may be substituted with halogen, hydroxyl or oxo are preferred. More specifically, for example, 3-methyl-2-butenyl, cyclopropyl, cyclobutyl, cyclopentyl, ethoxycarbonyl, carbamoyl, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, butylsulfonyl, (2-hydroxyethyl)sulfonyl, (2,2,2-trifluoroethyl)sulfonyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-fluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 2-oxopropyl, 2-oxobutyl, 2-aminoethyl, cyclopropylmethyl, 2-ethoxyethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, methylthiomethyl, 2-methylthioethyl, methylsulfonylmethyl, 2-methylsulfonylethyl, ethoxycarbonylmethyl and 2-(carbamoyloxy)ethyl groups are preferred. Of those, methyl, ethyl, propyl and methylsulfonyl groups, inter alia, methylsulfonyl, are particularly preferred.
R2 signifies lower alkyl.
As R2, for example, methyl, ethyl propyl and isopropyl, in particular, methyl and ethyl, are preferred.
As preferred embodiments of the compounds of the present invention, for example, those in which A, B, C and D are same or differtent and signify methine group(s) which may be substituted with halogen, hydroxyl, lower alkylsulfonyl, or lower alkyl which may have a substituent selected from the group consisting of halogen, hydroxyl, amino, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, lower alkoxycarbonylamino, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, (lower alkylamino)sulfonylamino and (di-lower alkylamino)sulfonylamino; both 
are 1,4-piperidine-di-yl; and R1 is a lower alkenyl, cyclo(lower alkyl), lower alkoxycarbonyl or carbamoyl, or lower alkylsulfonyl which may be substituted with halogen, hydroxyl or oxo, or lower alkyl which may have a substituent selected from the group consisting of cyano, halogen, hydroxyl, oxo, amino, cyclo(lower alkyl), optionally fluorine-substituted lower alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, lower alkylsulfonylamino, (lower alkylcarbamoyl amino, (di-lower alkylcarbamoyl)amino, (lower alkylamino)sulfonylamino and (di-lower alkylamino)sulfonylamino can be named.
As the compounds of the present invention, for example, specifically the following are preferred;
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-propynyl)-1,3-dihydro-2H-benzimidazol-2-one.
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-propenyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-n-butyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-methyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methoxycarbonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-oxopropyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(dimethylaminosulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-n-propyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-acetyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methoxycarbonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylazetidin-3-yl)piperidin-4-yl]-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)azetidin-3-yl]-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-5-methyl-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-4-fluoro-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,
1-[1-(1-ethoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-fluoroethyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2,2-difluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(3,3,3-trifluoropropyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-prenyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(ethylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(isopropylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(n-butylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(ethoxycarbonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-oxo-n-butyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylthiomethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-methylsulfonylethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-methylthioethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-ethoxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-ethoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-methyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-methyl-4-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin -4-yl]-3-methyl-4-(methylsulfonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-ethyl-4-(methylsulfonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycatbonylpiperidin-4-yl)piperidin-4-yl]-3-ethyl-4-(ethylsulfonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-methyl-4-(methoxycarbonylamino)methyl-1,3-dihydro-2H-benzimidazol-2-one
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-ethyl-4-(methoxycarbonylamino)methyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-4-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-5-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-6-hydroxy-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-5-bromo-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-6-fluoro-1,3-dihydro-2H-benzimidazol-2-one, and
1-[1-(1-ethoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(ethoxycarbonyl)-1,3-dihydro-2H-benzimidazol-2-one.
Of those, particularly
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-methyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methoxycarbonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-n-propyl-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methoxycarbonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(ethylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-5-methyl-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-4-fluoro-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-6-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2-fluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-(2,2-difluoroethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-methyl-4-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-methyl-4-(methylsulfonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-ethyl-4-(methylsulfonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-ethyl-4-(ethylsulfonylmethyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-methyl-4-(methoxycarbonylamino)methyl-1,3-dihydro-2H-benzimidazol-2-one and
1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-3-ethyl-4-(methoxycarbonylamino)methyl-1,3-dihydro-2H-benzimidazol-2-one are preferred.
The production methods of the compounds of the present invention are explained hereunder.
Those compounds of the present invention which are represented by the general formula [I] can be prepared, for example, by the production method 1, 2, 3 or 4 shown in the following.
Production Method 1
A compound represented by the general formula [I] or a salt thereof can be prepared by a process comprising reacting a compound of a general formula [II]
in which a, b, c and d are same or differtent and signify methine group(s) or nitrogen atom, said methine group(s) being optionally substituted with cyano, halogen, optionally protected hydroxyl, cyclo(lower alkyl), lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, aminosulfonyl, lower alkylaminosulfonyl or di(lower alkyl)aminosulfonyl, or lower alkyl which may have a substituent selected from the group consisting of halogen, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, lower alkoxycarbonylamino, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, (lower alkylamino)sulfonylamino, (di-lower alkylamino)sulfonylamino, (lower alkylaminosulfonyl)(lower alkyl)amino, (di-lower alkylaminosulfonyl)(lower alkyl)amino, and optionally protected hydroxyl, amino and lower alkylamino; R1p signifies lower alkenyl, lower alkynyl, cyclo(lower alkyl), lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, aminosulfonyl, lower alkylaminosulfonyl or di(lower alkyl)aminosulfonyl, or lower alkylsulfonyl which may be substituted with halogen, optionally protected hydroxyl or oxo, or lower alkyl which may have a substituent selected from the group consisting of cyano, halogen, oxo, cyclo(lower alkyl), optionally fluorine-substituted lower alkoxy, di(lower alkyl)amino, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di(lower alkyl)carbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di(lower alkyl)carbamoyloxy, aminosulfonyl, lower alkylaminosulfonyl, di(lower alkyl)aminosulfonyl, lower alkylsulfonylamino, (lower alkylcarbamoyl)amino, (di-lower alkylcarbamoyl)amino, (lower alkylamino)sulfonylamino and (di-lower alkylamino)sulfonylamino, and optionally protected hydroxyl, amino and lower alkylamino; E
and R2 have the earlier given significations] with a compound represented by a general formula [III]
[in which L1 signifies a leaving group; E and R2 have the earlier given significations] to form a compound represented by a general formula [IV]
[in which a, b, c, d, E, 
R1p and R2 have the earlier given significations] and if necessary removing the protective group(s).
Examples of the leaving group L1 include halogen atoms such as chlorine, bromine or iodine; organic sulfonyl groups such as methanesulfonyl, ethanesulfonyl and benzenesulfonyl; organic sulfonyloxy groups such as methanesulfonyloxy, trifluoromethanesulfonyloxy and p-toluenesulfonyloxy; and 1-imidazolyl group.
The reaction between a compound of the formula [II] and a compound of the formula [III] is usually conducted by using equimolar amounts of the two or using either one of them in slight molar excess, in an inert solvent which is not detrimental to the reaction.
As the inert solvent, for example, ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; and aprotic polar solvents such as dimethylformamide, N,N-dimethylacetamide and acetonitrile are preferred.
It is preferred to carry out the above reaction in the presence of a base. As the base, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and lithium diisopropylamide; or inorganic bases such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogencarbonate are preferred.
The use rate of the base is 1 mole or molar excess, preferably 1 to 3 moles, per mole of the compound represented by the general formula [II].
The reaction temperature is usually from xe2x88x9278xc2x0 C. to 150xc2x0 C., preferably from 0xc2x0 C. to 80xc2x0 C.
The reaction time is usually from 5 minutes to 7 days, preferably from 30 minutes to 24 hours.
After termination of the reaction, customary treatment(s) are conducted to provide crude product of a compound of the general formula [IV].
Where amino, hydroxyl or a like group(s) which do not participate in the reaction are present in the above reaction, such amino or hydroxyl groups are preferably protected with suitable amino- or hydroxyl-protective groups before conducting the reaction, which protective group(s) are removed after the reaction.
As amino-protective groups, for example, aralkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and trityl; lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl and pivaloyl; benzoyl; arylalkanoyl groups such as phenylacetyl and phenoxyacetyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and tert-butoxycarbonyl; aralkyloxycarbonyl groups such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and phenethyloxycarbonyl; lower alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl; phthaloyl; and aralkylidene groups such as benzylidene, p-chlorobenzylidene and o-nitrobenzylidene may be named. In particular, acetyl, pivaloyl, benzoyl, ethoxycarbonyl and tert-butoxycarbonyl groups are preferred.
As hydroxyl-protective groups, for example, substituted silyl groups such as trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; lower alkoxymethyl groups such as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl groups such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and trityl; and acyl groups such as formyl and acetyl may be named. In particular, methoxymethyl, tetrahydropyranyl, trityl, trimethylsilylethoxymethyl, thert-butyldimethylsilyl and acetyl groups are preferred.
Where a compound represented by the general formula [IV] contains protected amino or hydroxyl group(s), a compound represented by the general formula [I] can be prepared therefrom by removing the protective group(s). Deprotection of said functional group(s) can be effected following a method known per se, for example, the method described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons, (1981) or a method analogous thereto such as, for example, solvolysis using an acid or a base, chemical reduction using metal hydride complex or the like, or catalytic reduction using palladium-on-carbon catalyst, Raney nickel catalyst or the like.
Production Method 2
A compound represented by the general formula [I] or a salt thereof can be prepared by a process comprising subjecting a compound of a general formula [V]
[in which a, b, c, d, 
and R1p have the earlier given significations] and a compound of a general formula [VI]
[in which E, 
and R2 have the earlier given significations] to a reducting aminaton reaction to form a compound of a general formula [IV]
[in which a, b, c, d, E, 
R1p and R2 have the earlier given significations], and if necessary removing the protective group(s).
The reducing amination reaction between a compound of the formula [V] and a compound of the formula [VI] is usually conducted using equimolar amounts of the two or using either one of them in slight molar excess.
The reaction is usually conducted in an inert solvent. As the inert solvent, for example, alcohols such as methanol, ethanol, propanol and 2-propanol; ethers such as ethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene; aprotic polar solvents such as dimethylformamide, ethyl acetate, acetonitrile and hexamethylphosphoric triamide; and mixtures of the foregoing may be named.
The reaction temperature is usually from 0xc2x0 C. to the boiling point of used solvent, preferably from room temperature to 100xc2x0 C.
The reaction time usually ranges from 5 minutes to 48 hours, preferably from 10 minutes to 24 hours.
After termination of the above reaction, the reaction liquid may be used in the subsequent reducing reaction as it is or distilled off, or a compound which is expressed by a general formula [X]
[in which 
signifies a C3-C9 mono- or bi-cyclic aliphatic nitrogen-contaiing heterocyclic group which is optionally substituted with halogen or lower alkyl and which has a double bond between the ring carbon binding with 
and another ring carbon adjacent to said carbon; and a, b, c, E, 
R1p and R2 have the earlier given significations] is isolated by using customary separation means and subjected to the subsequent reducing reaction.
Said reducing reaction can be performed by using, for example, metal hydride complex such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride and the like, or by catalytic reduction using, for example, palladium-on-carbon catalyst, Raney-nickel catalyst and the like.
In particular, when a reducing agent which predominantly reduces imine/enamine, such as sodium cyanoborohydride, sodium triacetoxyborohydride or the like is used, the reaction liquid can be subjected to the reducing reaction as it is, without isolating the compound represented by the general formula [IX].
Where a metal hydride complex is used as the reducing agent, the use rate of the reducing agent usually ranges from 1 mole to molar excess, preferably from 1 to 5 moles, per mole of said imine.
In said reducing reaction, depending on the kind of reducing agent used, suitably a solvent may be used, for example, an inert solvent selected from alcohols such as methanol and ethanol; ethers such as dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran and diglyme; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane; aromatic hydrocarbons such as benzene and toluene; and their mixtures.
The reaction temperature usually ranges from xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to room temperature.
The reaction time usually ranges from 5 minutes to 7 days, preferably from 1 to 6 hours.
Furthermore, the hydrogen pressure in the catalytic reducing reaction is preferably from atmospheric to 5 atmospheres, and the use rate of the catalyst usually ranges from {fraction (1/100)} to 1, preferably from {fraction (1/100)} to {fraction (1/10)}, per 1 of the starting compound [X], by weight.
After termination of the reaction, customary treatment(s) are conducted to provide crude product of a compound of the general formula [IV].
Where amino, hydroxyl or like group(s) which do not participate in the reaction are present in the above reaction, such amino or hydroxyl groups are preferably protected with a suitable amino- or hydroxyl-protective groups before conducting the reaction, which protective group(s) are removed after the reaction.
Where a compound represented by the formula [IV] contains protected amino or hydroxyl group(s), a compound represented by the general formula [I] can be prepared therefrom by removing the protective group(s).
As for the amino- or hydroxyl-protective groups and the deprotection, those protective groups and deprotection means as described in connection with the production method 1 are applicable.
Production Method 3
A compound represented by the general formula [I] or a salt thereof can be prepared by a process comprising reacting a compound represented by a general formula [VII]
[in which a, b, c, d, E, 
and R2 have the earlier given significations] with a compound represented by a general formula [VIII]
R1pxe2x80x94L2xe2x80x83xe2x80x83[VIII]
[in which L2 signifies a leaving group, and R1p has the earlier given signification],
to form a compound represented by the general formula [IV]
xe2x80x83[in which a, b, c, d, E, 
xe2x80x83R1p and R2 have the earlier given significations] and if necessary removing protective group(s).
As the leaving groups indicated as L2, those leaving groups as exemplified for the leaving group L1 can be named.
The reaction of a compound of the general formula [VII] with a compound of the general formula [VIII] can be performed in the analogous manner to that of a compound of the general formula [II] with a compound of the general formula [III] as in the production method 1, applying similar reaction conditions and other features.
After termination of the reaction, customary treatment(s) are conducted to provide crude product of a compound of the general formula [IV].
Where amino, hydroxyl or a like group(s) which do not participate in the reaction are present in the above reaction, such amino or hydroxyl groups are preferably protected with suitable amino- or hydroxyl-protective groups before conducting the reaction, which protective group(s) are removed after the reaction.
Where a compound represented by the formula [IV] contains protected amino or hydroxyl group(s), a compound represented by the general formula [I] can be prepared therefrom by removing the protective group(s).
As for the amino- or hydroxyl-protective groups and the deprotection, those protective groups and deprotection means as described in connection with the production method 1 are applicable.
Production Method 4
A compound represented by the general formula [I] or a salt thereof can be prepared by a process comprising reacting a compound. of a general formula [IX]
[in which a, b, c, d, E, 
is R1p and R2 have the earlier given significations], with a compound selected from the group consisting of carbonyldiimidazole, triphosgene, diphosgene, methyl chloroformate, ethyl chloroformate, dimethyl carbonate and diethyl carbonate, to form a compound represented by the general formula [IV], 
[in which a, b, c, d, E, 
R1p and R2 have the earlier given significations], and if necessary removing protective group(s).
The reaction of a compound of the general formula [IX] with a compound selected from the group consisting of carbonyldiimidazole, triphosgene, diphosgene, methyl chloroformate, ethyl chloroformate, dimethyl carbonate and diethyl carbonate is usually conducted using a chemical equivalent or excessive amount of the compound selected from the group consisting of carbonyldiimidazole, triphosgene, diphosgene, methyl chloroformate, ethyl chloroformate, dimethyl carbonate and diethyl carbonate, to the compound of the general formula [IX].
This reaction may be conducted in the presence of a base, if necessary, preferred examples of the base including organic bases such as triethylamine, diisopropylethylamine and 4-dimethylaminopyridine; and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate and sodium hydrogenecarbonate.
The reaction is usually conducted in an inert solvent, examples of the inert solvent including alcohols such as methanol, ethanol, propanol and 2-propanol; ethers such as ethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; aromatic a hydrocarbons such as benzene, toluene, chlorobenzene and xylene; aprotic polar solvents such as dimethylformamide, ethyl acetate, acetonitrile and hexamethylphosphoric triamide; and mixtures of the foregoing.
The reaction temperature is usually from 0xc2x0 C. to the boiling point of used solvent, preferably from room temperature to 100xc2x0 C.
The reaction time usually ranges from 5 minutes to 48 hours, preferably from 10 minutes to 24 hours.
After termination of the reaction, customary treatment(s) are conducted to provide crude product of a compound of the general formula [IV].
Where amino, hydroxyl or a like group(s) which do not participate in the reaction are present in the above reaction, such amino or hydroxyl groups are preferably protected with suitable amino- or hydroxyl-protective groups before conducting the reaction, which protective group(s) are removed after the reaction.
Where a compound represented by the formula [IV] contains protected amino or hydroxyl group(s), a compound represented by the general formula [I] can be prepared therefrom by removing the protective group(s).
As for the amino- or hydroxyl-protective groups and the deprotection, those protective groups and deprotection means as described in connection with the production method 1 are applicable.
Isolation and purification of those compounds expressed by the general formula [I], [IV] or [X], which are obtained by the above-described methods, can be accomplished by customary separation means such as column chromatography using silica gel, adsorption resin and the like, liquid column chromatography, solvent extraction or recrystallization, reprecipitation and the like, conducted either singly or in combination.
Those compounds expressed by the general formula [I] can be converted to pharmaceutically acceptable salts by conventional means. Conversely, conversion from such salts to free compounds can be performed by conventional means.
As those compounds expressed by the general formulae [II], [III], [V], [VI], [VII], [VIII] or [IX] and other starting compounds, for example, commercially available ones may be used, or they can be prepared by methods taught in literature [e.g., see Tetrahedron, Vol.54, p.487 (1998); International Publication WO96/13262; Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons (1981)], methods analogous thereto or those described in working or referential examples.
Usefulness of compounds of the present invention is proven, for example, by the following pharmacological test esxamples.
Pharmacological Test 1 (in vitro Function Assay)
cDNA which codes a human m4 receptor gene [cf. Science, Vol.237, pp.527-532 (1987)] was cloned into an expression vector pcDNA3 (Invitrogen Co.) in which the promoter was modified to human EF-1a, to prepare pEFcDNA3/hm4. Also cDNA which codes a-subunit gene of GTP-bound protein Gi2 was cloned into an expression vector pIRESpuro (CLONTECH Co.) to prepare pIRES-puro/Gi. Then pEFcDNA3/hm4 and pIRES puro/Gi were introduced into CHO cells, together with pCRE-Luc(CLONTECH Co.) and pcDNAhyg (Invitrogen Co.), to provide a stable strain (hm4/Gi/Luc/CHO) which was resistant to selective drugs G418, puromysin and hygromysin B for selection.
This cell strain was cultured overnight to confluent in 96 well view plate (PACKARD CO.).
This cell strain was loaded with calcium indicator Fluo-3 acetoxymethyl ester (Molecular Probes Co.), then the intracellular calcium concentration was measured by transient increase in intracellular fluorescence intensity, elicited by each test compound in the presence of ATP (10 nM), using FLIPR(trademark) (Molecular Device Co.). The maximum intracellular fluorescence intensity of each test compound (10 mm) was determined as % agonist activity, the rise in the intracellular fluorescence intensity elicited by carbachol (10 mm) as the control drug being set as 100% value. The results are shown in Table 1.
From the above, it is demonstrated that the compounds of the present invention possess M4 receptors-stimulating action.
Pharmacological Test 2 (Mouse Tail Pinch Test)
Analgesic action of compounds of the invention was evaluated by tail pinch method (Haffner method). In the test, male mice of ICR strain (5-6 weeks old, Nippon SLC Co.). Root protions of mice"" tails were pinched with an arterial Kle mme, and latency until each mouse bit at the Kle mme was measured. The analgetic effect was recorded based on the following equation. For preventing tissue damage, the cut-off time was set to be 6 seconds. The analgesic effect was calculated according to the following equation:
Analgesic effect (%)=[(Latency after drug administrationxe2x88x92latency before drug administration)/(cut-off time 6 secondsxe2x88x92latency before drug administration)]xc3x97100.
Test compounds were subcutaneously administered at a dosage of 1 mg/kg each, and their analgetic action was examined according to the above-described method. In consequence, for example, as for the compounds of Examples 4, 10, 11, 13 and 14, 18%-100% analgetic effect was observed.
From the above results, compounds of the present invention are found to stimulate muscarinic acetylcholine receptors M4 and are useful as, for example, analgesics for diseases accompanying pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain or neuralgia; or as agents for treating tolerance to narcotic analgesics represented by morphine, dependence on narcotic analgesics represented by morphine, itching, dementia, irritable bowel syndrome, schizophrenia, glaucoma, pollakiuria, urinary incontinence, cholelithiasis, cholecystitis, functional dyspepsia and reflux esophagitis.
Those compounds represented by the general formula [I] can be administered orally or parenterally, and when they are formulated into preparation forms suitable for such administration, they can be offered as, for example, analgesic or as agents for treating tolerance to narcotic analgesics represented by morphine, dependence on narcotic analgesics represented by morphine, itching, dementia, irritable bowel syndrome, schizophrenia, glaucoma, pollakiuria, urinary incontinence, cholelithiasis, cholecystitis, functional dyspepsia and reflux esophagitis. In clinical use of compounds of the present invention, it is also possible to add pharmaceutically acceptable adjuvants in accordance with individual form of administration and formulate them into various preparation forms before administration. As adjuvants in such occasions, various adjuvants customarily used in the field of pharmaceutical preparations can be used, which include, for example, gelatin, lactose, white sugar, titanium dioxide, starch, crystalline cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, white vaseline, magnesiu mmetasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid esters, polysorbate, sucrose fatty acid esters, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin and hydroxypropyl cyclodextrin.
The forms of the pharmaceutical preparations obtained in the form of the mixtures with these adjuvants include solid pharmaceutical preparations such as, for example, tablets, capsules, granules, powders and suppositories; and liquid pharmaceutical preparations such as, for example, syrups, elixirs and parenteral solutions, and they can be prepared according to conventional methods in the pharmaceutical preparation field. In the case of the liquid pharmaceutical preparations, they may be dissolved or suspended in water or other suitable media at the time of use. Furthermore, particularly in the case of the parenteral solutions, they may be dissolved or suspended, if necessary, in a physiological saline solution or a glucose solution, and a buffer or a preservative may also be added.
These pharmaceutical preparations can contain the compounds of the present invention in a proportion of 0.1 to 100% by weight, preferably 0.1 to 50% by weight based on the whole pharmaceutical components. These pharmaceutical preparations may contain other compounds which are therapeutically active.
When the compounds of the present invention are used as analgesic or agents for treating tolerance to a narcotic analgesics represented by morphine, dependence on a narcotic analgesics represented by morphine, itching, dementia, irritable bowel syndrome, schizophrenia, glaucoma, pollakiuria, urinary incontinence, cholelithiasis, cholecystitis, functional dyspepsia and reflux esophagitis, their dosages and administration frequency differ depending on sex, age, body weight and conditions of individual patients and also on the kind and extent of intended therapeuric effect. In general, for oral administration it is preferred to administer 0.01-10 mg/kg/day for adult in single or divided doses, and for parenteral administration, 0.003-3 mg/kg/day, in single or divided doses. Depending on patient""s conditions, prophylactic administration is permissible.
Best Mode for Carrying Out the Invention
The present invention is more specifically explained, referring to working examples and referential examples, which should not be construed to restrict the scope of the invention in any way.